This is a revised competitive renewal for CA80964 - Mechanisms that regulate tumor-specific immune responses. In the past 5 years we have made considerable progress on the aims of our previous proposal and acquired a number of insights that we consider to be highly relevant to improving the treatment of patients with cancer. These insights pertain to the three different areas noted below. The overarching hypothesis of this proposal is that tumors fail to regress, or progress following initial regression, because of the presence of active, potent suppressive mechanisms and/or the failure to maintain adequate numbers of therapeutic T cells in the cancer-bearing host. Building on our progress, we propose to address the following three specific aims: Aim 1: To investigate the mechanisms responsible for the loss of therapeutic anti-tumor function following multiple vaccinations and identify strategies to boost anti-tumor immunity without loss of therapeutic function. Aim 2: To investigate the mechanisms responsible for tumor recurrence after successful immunotherapy and develop methods to prevent/treat tumor recurrence. Aim 3: To evaluate whether proteasomal-dependant regulation of immune targets represents a novel immune escape mechanism and develop strategies to treat antigen-loss variants. IMPACT: Translation of Laboratory results to the clinic: Since 2007 we have completed two pilot clinical trials that combined chemotherapy-induced lymphodepletion with adoptive transfer of PBMC (reconstitution) and vaccination with encouraging results. The preclinical platform for these trials was developed in the prior funding cycle of this award. In early 2009 we opened 2 new investigator-initiated clinical trials based on findings supported by this award. A third investigator-initiated FDA-approved clinical trial has been held back because of vaccine issues and the CD4-depletion study, mentioned above, is awaiting availability of Zanolimumab (humanized anti-CD4 in Phase III clinical trials).